Degenerative brain diseases are age-related diseases caused by the dysfunction of neurons, and social interest in degenerative brain diseases has increased with a rapid increase in the aging population. Degenerative brain diseases are classified according to major clinical symptoms and affected brain areas, and include Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis.
Degenerative brain diseases are known to be caused by the death of neurons that are most important in the transmission of information in the cerebral nervous system, defects in the formation or functions of synapses that transmit information among neurons, and abnormalities or decreases in the electrical activity of neurons, but these are still difficult to be radically treated, and the causes thereof are also still unclear.
With the recent development of cell and molecular biology, the causes of degenerative brain diseases and the development of therapeutic agents against degenerative brain diseases have been actively investigated. Studies on the development of therapeutic agents against degenerative brain diseases have been focused mainly on the following: (1) stimulation of cholinergic activity; (2) antagonism against NMDA (N-methyl-D-aspartate) receptors; (3) molecular and cell biological studies on the metabolism of β-amyloid or Tau protein, and the development of vaccine and therapeutic antibodies against β-amyloid-generating protein as an antigen; (4) induction of the expression of neurotrophic factor; (5) development of antioxidants capable of inhibiting causative protein-induced oxidative damage to neuronal cells; and (6) development of anti-inflammatory drugs capable of inhibiting inflammatory responses caused by the excessive infiltration and activity of inflammatory cells (Sonkusare et al., Pharmacological Research, 51(1), 1-17, 2005; Stanaione et al., Ann 1st Super Sanita, 47(1), 49-54, 2011; Halperin et al., Neurotherapeutics, 6(1), 128-140, 2009).
An AChE inhibitor, that is a cholinergic agent, inhibits the degradation of ACh and thus restore the activity of cholinergic neurotransmitters. As such AChE inhibitors, tarcrien, donepezil, rivastigmine and galanthamine were approved by the FDA, and are currently on the market.
It was reported that oxidative stress is an important cause of degenerative brain diseases of the central nervous system, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease (Jin D Q et al, Biochemical and Biophysical Research Communications, 331, 1264-1269, 2005; Lim C S et al, Biological and Pharmaceutical Bulletin, 29, 1212-1216, 2006).
The number of patients with ischemic vascular diseases (myocardiac infarction, stroke, and thrombosis) in the world was 25 million in 2007, and is expected to continue to increase to 28 million in 2017 (DataMonitor, 2007). In most of OECD countries, ischemic vascular diseases were the first leading cause of death (226.6 persons per 100,000 persons in the year 2004), followed by cancer (165.6 persons). Stroke is divided into hemorrhagic stroke characterized by brain tissue injury caused by disruption of brain blood vessels, and ischemic stroke that is brain infarction caused by blockage of the flow of blood into the brain. Stroke is a disease with a very high incidence, which is the first or second leading cause of death along with cancer in every year in Korea (the 2002 to 2008 data by the Korea National Statistical Office), and Korea ranks the second of OECD countries in terms of the rate of death caused by stroke. According to the 2008 report of the American Heart Association (AHA), 65.5 billion dollars are expended annually for stroke to treat and to care ischemic vascular diseases, but the size of the therapeutic agent market for stroke is only 1.3 billion dollars. Thus, active efforts have been made to develop therapeutic agents for ischemic stroke that will have a potential market size of 22 or more billion dollars if any therapeutic agents with proven efficacy are put on the market in a few years.
In Korea, stroke is the first leading cause of death, and ranks higher than those in highly developed countries, including the USA, Canada, Australia and the like. Stroke destroys the quality of life by causing damage to motor and sensory functions, and abnormalities in higher-order functions such as memory, learning, operation and deduction, and causes much mental and physical pains to patients and their family until patients die. In recent years, as the aging population has increased rapidly, the incidence of stroke and an increase in survival time after the onset of stroke becomes a big social problem. Thus, it is required to develop therapeutic drugs for alleviating the symptoms and treating stroke.
Despite the clinical significance of stroke and the big market size as mentioned above, the development of therapeutic agents for stroke is still insignificant, and clinically approved therapeutic agents for stroke include only tissue plasminogen activator (t-PA). Stroke is caused by various reasons, and comprises various diseases with different etiologic factors including brain infarction, cerebral hemorrhage and subarachnoid hemorrhage and the like. In addition, stroke may be caused by various cerebrovascular diseases, including arteriosclerosis, cerebral amyloid angiopathy, and aortic dissection, and may also be caused by cardiogenic embolism due to arrhythmia or coronary artery disease. The causes of stroke are diverse as described above, but in terms of cell biology, it is considered that a decrease in blood supply and the resulted cell death are the common mechanism. For this reason, the understanding of mechanism for ischemic neuronal cell death is a core technology to develop the therapeutic strategies for stroke prevention, control, and treatment.
In Korea and other countries, many research groups have made efforts to prevent brain diseases by studying the mechanism of neuronal death as mentioned above. In the case of stroke, a distinctive therapeutic agent has not yet been developed, and many clinical doctors are reluctant to use even t-PA, the sole therapeutic agent that is clinically used to dissolve thrombi produced in brain blood vessels, because of its side effects such as cerebral hemorrhage. Until now, many research groups have attempted to develop a therapeutic agent for stroke based on either an antagonist against glutamic acid receptor that is an excitatory neurotransmitter, or an antioxidant, but such attempts have failed due to insignificant efficacy or toxicity of drugs.
The time taken for a stroke patient to reach a hospital emergency room after the onset of stroke is usually several hours or more. Within several minutes to several hours after the onset of stroke, neuronal cells are primarily damaged by excitatory neurotoxicity caused by the excessive release of glutamic acid, and are secondarily damaged by exposure to the excessive oxygen and nitrogen radicals produced with the passage of time. After a few tens of hours, the neuronal cells are continuously and severely damaged by inflammatory responses, and in this case, it is clinically meaningless to use an excitatory neurotoxicity inhibitor.
As mentioned above, stroke is not a disease caused by a single factor, but is a disease that causes brain injury by various pathways and mechanisms of cell death. In recent years, there have been attempts to obtain a synergistic therapeutic effect against stroke by the use of drugs with different mechanisms in combination. For example, the administration of aspirin in combination with dipyridamole showed a favorable prognosis for stroke compared to the administration of aspirin alone (Chatuvedi S., Clin Therap, 30(7), 1196-205, 2008). In addition, a combination of 17β-estradiol and tPA extended the therapeutic time window in ischemic stroke patients, because 17β-estradiol reduced cerebral hemorrhage caused by increased expression of urokinase, MMP2 and MMP9 caused by tPA (Liu R. et al., J Pharmacol Exp Ther, 332(3), 1006-12, 2010). The administration of Memantine (that is an NMDA receptor antagonist) in combination with Clenbuterol (that is beta-adrenalin beta 2 receptor agonist) showed a synergistic effect on the inhibition of ischemic brain injury in a permanent focal ischemic model. Also, the administration of memantine in combination with the calcium ion blocker Topiramate showed a synergistic effect on the inhibition of hypoxia-induced brain injury in neonatal rats (Culmsee C. et al., Stroke, 35(5), 1197-202, 2004). However, such studies are mostly intended to alleviate symptoms, and did not show synergistic effects based on protective mechanisms for brain tissue.
In order to understand ischemic brain tissue injury caused by ischemia and develop a drug for inhibiting this brain tissue injury, the mechanism and pathway of brain tissue injury after ischemia should be understood. Generally, brain cell injury or death after ischemia is caused by various factors. For example, it is known that excitotoxicity, peri-infract depolarization, oxidative stress, and inflammation are associated with the development of ischemic brain injury (Dirnagl et al., Trends Neurosci., 22, 391-397, 1999). Thus, it is crucial to understand the very diverse temporal profiles (e.g., onset and duration) and to properly interrupt their pathopathological cascades.
Neuronal death by excitotoxicity can be inhibited by a glutamate receptor antagonist, and ionic receptors on which glutamate acts are AMPA (α-amino-3-hydroxy-5-methyl-4-iso-xazolepropionic acid), kainate, and NMDA (N-methyl-D-aspartate) receptors. Particularly, many studies on cell death by NMDA receptor activity have been conducted (Standridge J. B., Clin. Ther., 26(5), 615-630, 2004). However, despite such efforts, the NMDA receptor blockers were not successful in clinical trials, because they had insignificant effects or were toxic. The NMDA receptor blocker MK-801 significantly reduced ischemic brain injury, but had a great disadvantage of a brief therapeutic time window. MK-801 showed a neuron protection effect in rats and gerbils only when it was administered within 1 hour after onset of focal ischemia (Margaill et al., J Cereb Blood Flow Metab, 16, 107-113, 1996; Hatfield R H et al., Eur J Pharmacol, 216, 1-7, 1992). Also, MK-801 delays postischemic neuronal death, but does not improve either neurological recovery or endpoint survival after several weeks of treatment (Valtysson J. et al., Acta Neurochir (Wien), 129, 58-63, 1994; Von Lubitz D K et al., Eur J Pharmacol, 233, 95-100, 1993). Receptors of the excitatory neurotransmitter glutamic acid include AMPA receptor together with NMDA receptor. Antagonists for the AMPA receptors did not show significant protective effects against neurological deficit at 28 days after MCAO (Colbourne F et al., Stroke, 30, 662-668, 1999). The short therapeutic window and lack of long-term therapeutic effect of NMDA or AMPA receptor antagonists suggest that such receptors perform only a transient role in the early ischemic cascade. Thus, other pathophysiological processes that are not affected by these treatments are thought to contribute to the delayed cerebral ischemic damage.
As various degenerative diseases, oxidative stress has a very great effect on the death or loss of function of cells in stroke. Thus, studies on the therapeutic effects of antioxidants for ischemic stroke have been actively conducted (Salama M. et al., Co-Enzyme Q10 to Treat Neurological Disorders: Basic Mechanisms, Clinical Outcomes, and Future Research Direction. CNS Neurol Disord Drug Targets. 2013; Rodrigo R. et al., Oxidative Stress and Pathophysiology of Ischemic Stroke: Novel Therapeutic Opportunities. CNS Neurol Disord Drug Targets. 2013). In Japan, Edaravone having antioxidant effect as its major mechanism is put on the market as a therapeutic agent for stroke (Firuzi O et al., Curr Med Chem., 18(25), 3871-88, 2011; Yoshida H. et al., CNS Drug Rev., 12(1), 9-20. 2006).
Several hours after excitatory neurotoxicity after ischemia, an inflammatory response is initiated in the injured brain area, and continued for several days to several weeks to worsen brain injury. Thus, in recent years, attempts to treat ischemic stroke using anti-inflammatory agents have been actively made (Price C J et al., J Neurol Neurosurg Psychiatry, 74, 1476-1484, 2003; Salama M, Co-Enzyme Q10 to Treat Neurological Disorders: Basic Mechanisms, Clinical Outcomes, and Future Research Direction. CNS Neurol Disord Drug Targets. 2013; Rodrigo R. et al., Oxidative Stress and Pathophysiology of Ischemic Stroke: Novel Therapeutic Opportunities. CNS Neurol Disord Drug Targets. 2013). Also, it was recently reported that inflammatory cells infiltrated from blood vessels plays a major role in the aggravation of brain injury in ischemic stroke (Kang G H et al., J Neurol Sci., 15, 318(1-2), 25-30, 2012; Choi I Y et al., Am J Pathol, 179(4), 2042-52, 2012; Choi Y K et al., Free Radic Res., 44(8), 925-35, 2010; Choi I Y et al., Free Radic Res., 44(5), 541-51, 2010; Lee J C et al., Glia, 50(2), 168-81, 2005). In addition, it was reported that anti-inflammatory responses mediated by cannabinoid B2 receptor inhibit damage to ischemic brain tissue (Choi I Y et al., Am J Pathol, 182(3), 928-39, 2013).
Thus, it is considered that the development of drugs having various cell protection activities is essential for complete treatment of stroke. To achieve this purpose, that is, to develop a pleiotrophic therapeutic drug having various cell protection mechanisms, the present inventors have developed a derivative of (1S)-(−)-verbenone. (1S)-(−)-verbenone is a natural anti-aggregation pheromone generated by bark beetles from a host tree resin precursor, alpha-pinene. Essential oils containing (1S)-(−)-verbenone have been reported to exhibit biological activities such as antimicrobial activity or insecticidal activity (Bernarde W A, Z Naturforsch C, 65, 588-93, 2010; Martinez-Velazquez M., J Med Entomol, 48, 822-827, 2011). In addition, WO 2000/63159 discloses that verbenone[(1S,5S)-4,6,6-trimethylbicyclo[3.3.3]hept-3-en-2one) and its derivatives have anti-inflammatory effects in the airway.
However, the above patent document neither discloses nor suggests the effects of verbenone derivatives on the reduction of neuronal death and oxidative stress, the inhibition of ischemic brain injury and the inhibition of migration of inflammatory cells.
Accordingly, the present inventors have measured NMDA-induced excitotoxicity and cell death in a hypoxic-ischemic rat model in order to examine the effects of verbenone derivatives on the reduction of neuronal death and oxidative stress and the inhibition of ischemic brain injury and inflammatory responses, and performed an experiment on the antioxidant activities of verbenone derivatives. As a result, the present inventors have first found that verbenone derivatives have an effect on the treatment of degenerative brain diseases. More specifically, the present inventors have found that verbenone derivatives according to the present invention reduce neuronal death and oxidative stress, and exhibit excellent effects on the inhibition of ischemic brain injury and inflammatory responses in vivo, thereby completing the present invention.